rs398122360

Positions:

• chr7-27101154-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_006735.4(HOXA2):​c.703C>T​(p.Gln235Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOXA2 NM_006735.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.36

Genes affected

HOXA2 (HGNC:5103): (homeobox A2) In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.378 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-27101154-G-A is Pathogenic according to our data. Variant chr7-27101154-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 88845.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-27101154-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA2	NM_006735.4	c.703C>T	p.Gln235Ter	stop_gained	2/2	ENST00000222718.7	NP_006726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA2	ENST00000222718.7	c.703C>T	p.Gln235Ter	stop_gained	2/2	1	NM_006735.4	ENSP00000222718	P1
HOXA2	ENST00000612779.1	n.1533C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Microtia with or without hearing impairment Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
Vest4		0.95
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398122360; hg19: chr7-27140773;